Effect of antihypertensive treatment Lisinopril on central arterial stiffness and cognitive functions in Dahl‐S rat model of vascular dementia: Development of new models and analysis methods/validation of pre‐clinical methods. (7th December 2020)

• Record Type: Journal Article
• Authors: Fedorova, Olga V.; Fenner, Rachel C.; Grigorova, Yulia N.; McDevitt, Ross; Juhasz, Ondrej; Ajamu, Samuel; Wei, Wen; Zernetkina, Valentina I.; Petrashevskaya, Natalia; Long, Jeffrey M.; Rapp, Peter R.; Lakatta, Edward G.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.044681
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Dahl salt‐sensitive rats (DSS) represent a model of vascular dementia, because they demonstrate an age‐associated increase in blood pressure (BP) and central arterial stiffness (CAS) accompanied by cognitive decline independent of a high salt intake. We hypothesized that treatment with an anti‐hypertensive drug ACE inhibitor Lisinopril will lower CAS and improve cognitive function in the adult hypertensive DSS. Method: Male DSS were kept on a normal salt diet for 12 months. Six‐month old rats received vehicle (control; DSS‐C; n = 20) or Lisinopril (15 mg/kg/day; DSS‐LIS; n = 20) for 6‐mo. Systolic BP (SBP), pulse wave velocity (PWV), a marker of CAS (by Doppler echocardiography), open field test (OFT) to assess anxiety‐like behavior and locomotion, and cued reaction time task (CRTT) to assess executive functioning were performed at BL (before treatment), after 3 and 6‐mo of treatment. Morris Water maze (MWM) test was performed to assess hippocampal spatial memory. Aortae were stained for elastin and collagen (immunohistochemistry). Statistical analysis: 2‐way ANOVA repeated measures and t‐test; data presented as mean ± SEM. Result: All non‐treated DSS were hypertensive. DSS‐LIS have lower SBP vs. BL and vs. age‐matched DSS‐C. PWV was lower in 12‐mo DSS‐LIS vs. BL and vs. age‐matched DSS‐C (Table). In MWM, DSS‐LIS had a higher path efficiency and traveled shorter distance to find the invisible platform vs. DSS‐C. In CRTT, DSS‐LIS had less premature responses than DSS‐C 3‐mo post treatment (Table). There was no change in total distance and distance traveled in the center in OFT at all time points in DSS‐LIS vs. DSS‐C (Table). 12‐mo old DSS‐LIS had lower heart and aortic weight, less aortic medial wall collagen and greater elastin/collagen ratio vs. DSS‐C (Table). Conclusion: Chronic treatment with Lisinopril effectively lowered SBP, CAS and reduced aortic collagen in aged hypertensive DSS rats. Lisinopril resulted in improved hippocampal spatial memory and reduced impulsive behavior demonstrating a beneficial cognitive effect in the DSS model of vascular dementia. Further studies will need to elucidate the effect of Lisinopril on cerebral blood vessels and whether ACE inhibitor has a direct effect of the brain in addition to its effect on CAS. Supported by the Intramural Research Program of the NIA/NIH.